Clopidogrel salt and polymorphic forms thereof

ABSTRACT

The invention relates to methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H) acetate naphthalene-1,5-disulfonate or a polymorphic form and/or a hydrate and/or a solvate thereof, to pharmaceutical compositions containing the same, and to the method of use thereof for inhibiting platelet aggregation.

The invention relates tomethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate, or a polymorphic form and/or ahydrate and/or a solvate thereof, to pharmaceutical compositionscontaining the same and to the method of use thereof for inhibitingplatelet aggregation.

U.S. Pat. No. 4,847,265, issued Jul. 11, 1989, discloses thedextrorotatory enantiomer of methylalpha-5-(4,5,6,7-tetrahydro-(3,2-C)thienopyridyl)(2-chlorophenyl)acetateor a pharmaceutically acceptable salt thereof. Specifically disclosedare the hydrochloride, hydrogen sulfate, hydrobromide, and taurocholatesalts.

U.S. Pat. No. 6,429,210, issued Aug. 6, 2002, discloses polymorphic FormII ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate hydrogen sulfate known as clopidogrel hydrogen sulfate.

WO 03/066637, published Aug. 14, 2003, discloses crystalline Forms I andII ofmethyl-(S)-(+)-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-C]pyridine-5-yl)acetatehydrochloride.

U.S. 2003/0114479, published Jun. 19, 2003, discloses crystalline FormsIII, IV, and V, and an amorphous form of clopidogrel hydrogen sulfate.

U.S. 2003/0225129, published Dec. 4, 2003, discloses crystalline FormsIII, IV, V and VI and an amorphous form of clopidogrel hydrogen sulfate.

The solid state physical properties of a pharmaceutical compound can beinfluenced by the conditions under which the compound is obtained insolid form. Solid state physical properties include, for example, theflowability of the milled solid which affects the ease with which thecompound is handled during processing into a pharmaceutical product.Another important solid state property of a pharmaceutical compound isits rate of dissolution in aqueous fluid. The rate of dissolution of anactive ingredient in a patient's stomach fluid can have therapeuticconsequences because it imposes an upper limit on the rate at which anorally administered active ingredient can reach the blood. Thesolid-state form of a compound may also affect its solubility,bioavailability, behavior on compaction, stability, or its electrostaticnature.

These physical properties of a pharmaceutical compound can be influencedby the conformation and orientation of molecules in the unit cell whichdefines a particular polymorphic form of a compound. The polymorphicform may give rise to thermal behavior different from that of theamorphous material or another polymorphic form. Thermal behavior ismeasured in the laboratory by such techniques as capillary meltingpoint, thermogravimetric analysis and differential scanning calorimetryand can be used to distinguish one polymorphic form from another. Aparticular polymorphic form may also give rise to distinct propertiesthat may be detectable by X-ray powder diffraction, solid-state ¹³CNMRspectrometry and infrared spectrometry.

The discovery of new crystalline polymorphic or amorphous forms of apharmaceutical compound provides an opportunity to improve the physicalor performance characteristics of a pharmaceutical product in that itenlarges the repertoire of materials that a formulation scientist hasavailable for designing, for example, a pharmaceutical dosage form of adrug with a targeted release profile or other desired characteristic.

The invention relates tomethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate of the formula I:

or a polymorphic form and/or a hydrate and/or a solvate thereof, andmore particularly to polymorphic Forms A, B, C, D, E, and F of thecompound.

Polymorphic Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane is characterized by anX-ray powder diffraction pattern with a peak at about 11.7 degreestwo-theta and more particularly with peaks at about 10.8, 11.7, and 13.0degrees two-theta. Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane is also characterized byan FTIR spectrum with peaks at about 1249, 1452, 1760, 2848, 2955, 3090,and 3490 cm⁻¹. Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane, which has a meltingpoint of about 165° C., exhibits an X-ray powder diffraction patternsubstantially as depicted in FIG. 1A and an FTIR spectrum substantiallyas depicted in FIG. 2.

Polymorphic Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate is characterized by an X-raypowder diffraction pattern with a peak at about 13.4 degrees two-theta.Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate is also characterized by anFTIR spectrum with peaks at about 600, 663, 1096, 1156, 3557, and 3605cm⁻¹. Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate, which has a melting pointof about 218° C., exhibits an X-ray powder diffraction patternsubstantially as depicted in FIG. 1B and an FTIR spectrum substantiallyas depicted in FIG. 3.

Polymorphic Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate ischaracterized by an X-ray powder diffraction pattern with a peak atabout 8.7 degrees two-theta and more particularly with peaks at about8.7, 14.1, and 27.4 degrees two-theta. Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate is alsocharacterized by an FTIR spectrum with peaks at about 529, 796, 1035,1175, 1221, 1251, and 1759 cm⁻¹. Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate, which has amelting point of about 228° C., exhibits an X-ray powder diffractionpattern substantially as depicted in FIG. 1C and an FTIR spectrumsubstantially as depicted in FIG. 4.

Polymorphic Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate is characterized by an X-raypowder diffraction pattern with a peak at about 24.1 degrees two-thetaand more particularly with peaks at about 9.3 and 24.1 degreestwo-theta. Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate is also characterized by anFTIR spectrum with peaks about 525, 711, 1026, 1170, 1243, and 1746cm⁻¹. Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate, which has a melting pointof about 228° C., exhibits an X-ray powder diffraction patternsubstantially as depicted in FIG. 1D and an FTIR spectrum substantiallyas depicted in FIG. 5.

Polymorphic Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate is characterized by an X-raypowder diffraction pattern with a peak at about 26.4 degrees two-thetaand more particularly with peaks at about 7.6, 11.0, 12.1, and 26.4degrees two-theta. Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate is also characterized by anFTIR spectrum with peaks at about 610, 764, 1026, 1196, 1224, and 1746cm⁻¹. Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate, which has a melting pointof about 224° C., exhibits an X-ray powder diffraction patternsubstantially as depicted in FIG. 1E and an FTIR spectrum substantiallyas depicted in FIG. 6.

Polymorphic Form. F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate is characterized by an FTIR spectrumwith peaks at about 565, 610, 764, 1028, 1751, and 2579 cm⁻¹. Form F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate exhibits an X-ray powder diffractionpattern substantially as depicted in FIG. 1F and an FTIR spectrumsubstantially as depicted in FIG. 7.

The present invention further relates to a pharmaceutical compositioncomprising:methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate or a polymorphic form and/or ahydrate and/or a solvate thereof, together with a pharmaceuticallyacceptable carrier, adjuvant, diluent, or vehicle.

The present invention further relates to a method for inhibitingplatelet aggregation which comprises administering to a patient in needthereof an effective amount ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate or a polymorphic form and/or ahydrate and/or a solvate thereof.

The present invention further relates to the use ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate or a polymorphic form and/or ahydrate and/or a solvate thereof in the preparation of a medicament forinhibiting platelet aggregation.

The present invention further relates to a method of reducingatherosclerotic events which comprises administering to a patient inneed thereof an effective amount ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate or a polymorphic form and/or ahydrate and/or a solvate thereof.

The present invention further relates to the use ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate or a polymorphic form and/or ahydrate and/or a solvate thereof in the preparation of a medicament forreducing atherosclerotic events.

FIG. 1A is an X-ray powder diffraction pattern of Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane.

FIG. 1B is an X-ray powder diffraction pattern of Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate.

FIG. 1C is an X-ray powder diffraction pattern of Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile hydrate.

FIG. 1D is an X-ray powder diffraction pattern of Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate.

FIG. 1E is an X-ray powder diffraction pattern of Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate.

FIG. 1F is an X-ray powder diffraction pattern of Form F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate.

FIG. 2 is an FTIR spectrum of Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane.

FIG. 3 is an FTIR spectrum of Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate.

FIG. 4 is an FTIR spectrum of Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(414)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate.

FIG. 5 is an FTIR spectrum of Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate.

FIG. 6 is an FTIR spectrum of Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate.

FIG. 7 is an FTIR spectrum of Form F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate.

Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane may be prepared byadding a solution ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate in ethanol to a solution of naphthalene-1,5-disulfonic acid inethanol and then adding heptane to the mixture. The solvents areevaporated, the residue is slurried with 1,4-dioxane/ethanol and thesolvents are evaporated to afford Form A.

Form. B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate may be prepared by addingmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate to a solution of naphthalene-1,5-disulfonic acid in ethanol,followed by the addition of 1,4,dioxane. Evaporation of the solventaffords a residue, that is seeded with Form A of the compound anddissolved in ethanol and then 1,4-dioxane is added followed byadditional seeds of Form A. The solvents are evaporated and the residueis crystallized from acetone to afford Form B.

Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile hydrate may be preparedby dissolving Form B of the compound in acetonitrile at about 45° C. andcollecting the Form C that precipitates upon cooling to roomtemperature.

Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate may be prepared bydissolving Form B of the compound in ethanol and collecting the Form Dthat precipitates upon cooling to about 0° C.

Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate may be prepared bysubjecting Form A of the compound to 75% relative humidity at about 40°C. for about two (2) weeks.

Form F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate may be prepared by dissolving Form Bof the compound in acetonitrile and collecting the Form F thatprecipitates by vapor diffusion upon placing a vial of the solution thusformed in a vial containing isopropylacetate.

Methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate can be prepared, for example, by the method described in U.S.Pat. No. 4,847,265, which is incorporated herein by reference, or by themethods described herein in the examples.

The following examples will further illustrate the invention with,however, limiting it thereto. All melting points are given in degreescentigrade (° C.) and are obtained by placing the sample in a glasscapillary. X-ray powder diffraction (XRPD) analyses were performed usinga Shimadzu XRD-6000 (with a tube voltage of 40 kV, an amperage of 40 mA,divergence and scattering slits set at 1°, the receiving slit set at0.15 mm, and a theta two theta continuous scan at 3°/min from 2.5 to 40°2 theta) X-ray powder diffractometer using CuKα radiation. Infraredspectrum were acquired on a Magna-IR 860 Fourier transform infrared(FT-IR) spectrophotometer equipped with an Ever-Glo mid/far IR source,and the samples were prepared by mixing the sample with KBr.

PREPARATION 1Methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate

A solution of clopidogrel hydrogensulfate (which can be preparedaccording to the methods described in U.S. Pat. No. 6,429,210 thecontents of which are incorporated herein by reference) was treated withan aqueous solution of sodium carbonate. The title compound wasextracted with diethyl ether and the solution was dried over MgSO₄ andthe solvent was removed under reduced pressure to afford the tit lecompound as a yellow gel.

EXAMPLE 1 Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane

A solution ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihythothieno[3,2-C]pyridine-5(4H)acetate of preparation 1 (1.8067 g in 25 mL of ethanol) (2.767 mL) wasadded to a naphthalene-1,5-disulfonic acid solution (1.0498 g in 10 mLif ethanol) (1.066 mL), followed by heptane (1.60 mL). The solution wasfiltered through a 0.2 μm nylon filter into a clean vial and left toevaporate under nitrogen. A gel formed which was slurried in a1,4-dioxane-ethanol (9:1) mixture (1.0 mL). The sample was then coveredwith Parafilm, perforated and allowed to evaporate. The solids whichformed were temperature cycled between 25-35° C., filtered and dried toafford 0.2408 g of the title compound, m.p. 165° C., which was analyzedby FTIR and XRPD.

EXAMPLE 2 Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]Pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate

Methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate of preparation 1 (1.3013 g) was added to anaphthalene-1,5-disulfonic acid solution in ethanol (1.0498 g in 10 mLof ethanol, 7.00 mL). Additional ethanol (3.00 mL) was added and mixturesonicated until complete dissolution was achieved. 1,4-Dioxane (10.0 mL)was added and the solution was filtered through a 0.2 μm nylon filterinto a clean vial. The sample was left to evaporate uncovered. A gelformed which was seeded with. Form A of Example 1, followed by theaddition of ethanol (1 mL). The mixture was slurried at 40° C. until itcompletely dissolved. 1,4-Dioxane (8 mL) was added, followed by seeds ofForm A of Example 1 and the mixture left to evaporate uncovered. Whitesolids and gel formed and heptane (3.0 mL) was added. The slurry wasfiltered and solids washed with acetone. Some of the solids (0.0923 g)were slurried in acetone (0.80 mL) at 45° C. The slurry completelydissolved so more of the solids were added and the mixture was slurriedat 45-46° C. The slurry was then filtered through a 0.2 μm nylon filterinto a clean vial, capped, and placed in a water bath at 54° C., whichwas then slowly cooled to ambient temperature. Solids precipitated andthe mixture was refrigerated, then filtered through a 0.2 μm filter, andsolids left in the vial were dried under nitrogen to afford the titlecompound, m.p. 218° C., which was analyzed by FTIR and XRPD.

EXAMPLE 3 Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate

Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate of Example 2 (0.1151 g) wasslurried in acetonitrile (0.800 mL) at 45° C. Once the slurry dissolved,additional compound of Example 2 was added. The title compoundprecipitated from solution after slowly being cooled to room temperatureto afford the title compound, m.p. 228° C., which was analyzed by FTIRand XRPD.

EXAMPLE 4 Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate

Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate of Example 2 (0.1074 g) wasslurried in ethanol (0.80 mL). Additional compound of Example 2 wasadded once the slurry completely dissolved. Solids precipitated from theslow cooled solution in a freezer to afford the title compound, m.p.228° C., which was analyzed by FTIR and XRPD.

EXAMPLE 5 Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate

Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane of Example 1 (0.0208 g)was placed in a 75% relative humidity chamber at 40° C. for two weeks toafford 0.0197 g of the title compound, m.p. 224° C., which was analyzedby FTIR and XRPD.

EXAMPLE 6 Form F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate

Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(414)acetate naphthalene-1,5-disulfonate hydrate of Example 2 (0.0616 g) wasdissolved in acetonitrile (1.0 mL) with sonication. The solution wasfiltered through a 0.21 am nylon filter into a clean vial which wasplaced in a larger vial containing isopropylacetate (2.0 mL). The largervial was capped and crystallization was afforded by vapor diffusion toafford the title compound in the form of an amorphous solid which wasanalyzed by FTIR and XRPD.

As disclosed in U.S. Pat. No. 4,847,265 and U.S. Pat. No. 5,576,328 (theentire contents of each of which is incorporated herein by reference)methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate and its pharmaceutically acceptable salts have been found topossess valuable pharmacological properties. In particular, they havebeen found to inhibit platelet aggregation and thus would be useful inreducing atherosclerotic events, such as myocardial infarction, stroke,and vascular death.

The compounds of the invention are generally administered to patientswhich include, but are not limited to, mammals such as, for example,man. It will also be apparent to those skilled in the art that acompound according to the invention can be coadministered with othertherapeutic or prophylactic agents and/or medicaments that are notmedically incompatible therewith.

The compounds of the invention can be prepared for pharmaceutical use byconventional pharmaceutical procedures that are well known in the art,that is, by formulating a pharmaceutical composition which comprisescompounds of the invention together with one or more pharmaceuticallyacceptable carriers, adjuvants, diluents or vehicles, for oraladministration in solid or liquid form, parenteral administration,topical administration, rectal administration, or aerosol inhalationadministration, and the like.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, the activecompound is admixed with at least one inert diluent such as starch,calcium carbonate, sucrose or lactose. These compositions may alsocontain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate, talc and the like.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such was water andliquid paraffin. Besides inert diluents, such compositions may alsocontain adjuvants, such as, wetting and suspending agents andsweetening, flavoring, perfuming, and preserving agents. According tothe invention, the compounds for oral administration also includecapsules of absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents, or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thesecompositions can also contain adjuvants such as stabilizing, preserving,wetting, emulsifying and dispersing agents.

Preparations according to the invention for topical administration oraerosol inhalation administration include dissolving or suspending acompound of the invention in a pharmaceutically acceptable vehicle suchas water, aqueous alcohol, glycol, oil solution or oil-water emulsion,and the like.

Preparations according to the invention for rectal administrationinclude suppositories prepared by using suitable carriers, e.g., cacaobutter, hardened oils, glycerides or saturated fatty acids, and thelike.

If desired, the compounds of the invention can further be incorporatedinto slow release or targeted delivery systems such as polymer matrices,liposomes, and microspheres.

The percentage of active component in such compositions may be varied sothat a suitable dosage is obtained. The dosage administered to aparticular patient is variable depending upon the clinician's judgmentusing as criteria: the route of administration, the duration oftreatment, the size and physical condition of the patient, the potencyof the active component, and the patient's response thereto. Aneffective dosage amount of the active component can thus readily bydetermined by the clinician after a consideration of all criteria andusing his best judgment on the patient's behalf. In general, a compoundof the instant invention is administered at a dose in the range of about0.01 to about 100 mg/kg body weight.

1.Methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate, or a polymorphic form and/or ahydrate and/or a solvate thereof.
 2. Polymorphic Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane according to claim
 1. 3.Polymorphic Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane according to claim 2having an X-ray powder diffraction pattern with a peak at about 11.7degrees two-theta.
 4. Polymorphic Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane according to claim 2having an X-ray powder diffraction pattern with peaks at about 10.8,11.7, and 13.0 degrees two-theta.
 5. Polymorphic Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane according to claim 2having an FTIR spectrum with peaks at about 1249, 1452, 1760, 2848,2955, 3090, and 3490 cm⁻¹.
 6. Polymorphic Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane according to claim 2having a melting point of about 165° C.
 7. Polymorphic Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane according to claim 2having an X-ray powder diffraction pattern substantially as depicted inFIG. 1A.
 8. Polymorphic Form A ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate 1,4-dioxane according to claim 2having an FTIR spectrum substantially as depicted in FIG.
 2. 9.Polymorphic Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim
 1. 10.Polymorphic Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 9 havingan X-ray powder diffraction pattern with a peak at about 13.4 degreestwo-theta.
 11. Polymorphic Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 9 havingan FTIR spectrum with peaks at about 600, 663, 1096, 1156, 3557, and3605 cm⁻¹.
 12. Polymorphic Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 9 havinga melting point of about 218° C.
 13. Polymorphic Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 9 havingan X-ray powder diffraction pattern substantially as depicted in FIG.1B.
 14. Polymorphic Form B ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(41-1)acetate naphthalene-1,5-disulfonate hydrate according to claim 9 havingan FTIR spectrum substantially as depicted in FIG.
 3. 15. PolymorphicForm C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile hydrate according toclaim
 1. 16. Polymorphic Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate according toclaim 15 having an X-ray powder diffraction pattern with a peak at about8.7 degrees two-theta.
 17. Polymorphic Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate according toclaim 15 having an X-ray powder diffraction pattern with peaks at about8.7, 14.1, and 27.4 degrees two-theta.
 18. Polymorphic Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate according toclaim 15 having an FTIR spectrum with peaks at about 529, 796, 1035,1175, 1221, 1251, and 1759 cm⁻¹.
 19. Polymorphic Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate according toclaim 15 having a melting point of about 228° C.
 20. Polymorphic Form Cofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate according toclaim 15 having an X-ray powder diffraction pattern substantially asdepicted in FIG. 1C.
 21. Polymorphic Form C ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate acetonitrile-hydrate according toclaim 15 having an FTIR spectrum substantially as depicted in FIG. 4.22. Polymorphic Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-e]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim
 1. 23.Polymorphic Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 22 havingan X-ray powder diffraction pattern with a peak at about 24.1 degreestwo-theta.
 24. Polymorphic Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 22 havingan X-ray powder diffraction pattern with peaks at about 9.3 and 24.1degrees two-theta.
 25. Polymorphic Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 22 havingan FRIT spectrum with peaks at about 525, 711, 1026, 1170, 1243, and1746-cm⁻¹.
 26. Polymorphic Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 22 havinga melting point of about 228° C.
 27. Polymorphic Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-q]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 22 havingan X-ray powder diffraction pattern substantially as depicted in FIG.1D.
 28. Polymorphic Form D ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 22 havingan FTIR spectrum substantially as depicted in FIG.
 5. 29. PolymorphicForm E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim
 1. 30.Polymorphic Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 29 havingan X-ray powder diffraction pattern with a peak at about 26.4 degreestwo-theta.
 31. Polymorphic Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 29 havingan X-ray powder diffraction pattern with peaks at about 7.6, 11.0, 12.1,and 26.4 degrees two-theta.
 32. Polymorphic Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 29 havingan FTIR spectrum with peaks at about 610, 764, 1026, 1196, 1224, and1746 cm⁻¹.
 33. Polymorphic Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 29 havinga melting point of about 224° C.
 34. Polymorphic Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 29 havingan X-ray powder diffraction pattern substantially as depicted in FIG.1E.
 35. Polymorphic Form E ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate hydrate according to claim 29 havingan FTIR spectrum substantially as depicted in FIG.
 6. 36. PolymorphicForm F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate according to claim
 1. 37.Polymorphic Form F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate according to claim 36 having an FTIRspectrum with peaks at about 565, 610, 764, 1028, 1751, and 2579 cm⁻¹.38. Polymorphic Form F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate according to claim 36 haying anX-ray powder diffraction pattern substantially as depicted in FIG. 1F.39. Polymorphic Form F ofmethyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)acetate naphthalene-1,5-disulfonate according to claim 36 having an FTIRspectrum substantially as depicted in FIG.
 7. 40. A pharmaceuticalcomposition comprising a compound according to claim 1 together with apharmaceutically acceptable carrier, adjuvant, diluent, or vehicle. 41.A method for inhibiting platelet aggregation which comprisesadministering to a patient in need thereof an effective amount of acompound according to claim
 1. 42. A method of reducing atheroscleroticevents which comprises administering to a patient in need thereof aneffective amount of a compound according to claim 1.